Months Of Growth Hormone Treatment Research Articles

Diffusion tensor imaging shows increased physis organization after growth hormone initiation in hypophosphatasia.

Hypophosphatasia is a rare heritable disorder of bone mineralization, with a spectrum of severity based on age of initial presentation. We describe the case of a 14-year-old boy with gene-confirmed inherited hypophosphatasia and growth hormone deficiency, who presented with short stature, unremarkable radiographs, and only minor physeal and metaphyseal changes on magnetic resonance (MR) imaging. Diffusion tensor imaging (DTI) before growth hormone initiation revealed abundant, non-parallel tracts in the physes and metaphyses with loss of the typical columnar organization. After 8months of growth hormone treatment, DTI scans revealed realigned, nearly parallel, longer physeal tracts; duplication of tract volume; and decreased and more typical fractional anisotropy values. DTI can thus visualize physeal tract changes over time, could be a more sensitive diagnostic technique in milder physeal abnormality cases, and may be a potential marker of growth hormone treatment response.

Growth hormone treatment for neurologic symptoms of post-acute sequelae of COVID-19.

Following SARS-CoV-2 infection, some patients develop lingering neurologic symptoms of post-acute sequelae of COVID-19 (PASC) that commonly include fatigue and "brain fog." PASC symptoms are also linked with reduced growth hormone (GH) secretion, but GH treatment has not been tested to relieve symptoms. We enrolled 13 adults with neurologic PASC symptoms and peak stimulated GH secretion less than 10 ng/mL (glucagon stimulation) in a pilot study to receive 9 months of daily GH injections and an additional 3 months of off-treatment assessment. We compared peak stimulated GH secretion at baseline and 12 months and assessed measures of cognition, metabolism, body composition, and physical performance over the first 6 months of treatment. Patient-reported outcomes of fatigue, quality of life, sleep, and mood were recorded at baseline and compared with timepoints at 6, 9, and 12 months. GH treatment was associated with significantly improved scores for Brief Fatigue Inventory, Multidimensional Fatigue Symptom Inventory, Quality of Life Assessment of GrowthHormone Deficiency in Adults, Profile of Mood States, and Beck Depression Inventory-II, with no significant change in Pittsburgh Sleep Quality Index. Six months of adjunct GH treatment was not associated with significant changes in cognition, body composition, resting energy expenditure, or physical performance. Peak stimulated GH secretion was not altered at 12 months following 9 months of GH treatment. GH treatment significantly improved neurologic symptoms in PASC patients but cognition, sleep, and physical performance were not significantly altered.

Very young children with Prader-Willi syndrome are refractory to growth hormone-associated decreases in free thyroxine levels.

The earlier initiation of growth hormone (GH) treatment for patients with Prader-Willi syndrome (PWS) who are younger than 2 years has become more prevalent. Because free thyroxine (FT4) levels are low during this period, GH may induce further reductions; however, limited information is currently available on this issue. Therefore, we herein performed age-dependent and time-course analyses of thyroid hormone levels in GH-treated PWS children. This retrospective analysis included genetically diagnosed PWS patients (N = 37, median age of 26 months). An age-dependent analysis was performed by subdividing subjects based on age [a younger group aged between 1 and 24 months (N = 16) and an older group between 25 and 84 months (N = 21)] and was followed by a multiple regression analysis with adjustments for sex and the cumulative GH dose per bodyweight. A time-course analysis of subjects who had not received levothyroxine during the first 18 months of GH treatment (N = 28) was conducted. A one-month treatment with GH decreased FT4 levels in the older group, but not in the younger group, and this was associated with increases in thyroid-stimulating hormone levels. A positive correlation was noted between age and decreases in FT4 levels independent of the cumulative GH dose per bodyweight. The time-course analysis revealed no changes in FT4 levels in the younger group, while transient decreases were observed in the older group. In conclusion, GH treatment causes age-dependent changes in FT4 levels. This result will help clinicians establish a therapeutic strategy to decide the necessity of levothyroxine supplementation in GH-treated children with PWS.

Copeptin in Growth Hormone-Treated Patients.

Growth hormone (GH) changes body composition, including increasing body water. GH is known to have an anti-natriuretic effect in the kidney, but little is known of its effect on arginine-vasopressin (AVP) release. We studied the effect of GH on AVP release by measurement of copeptin, a fragment from the same precursor protein, in GH-treated patients with GH deficiency. The study was designed as a retrospective cohort study of biobank samples from 34 patients substituted with GH between 1999 and 2004. Copeptin and insulin-like growth factor 1 (IGF-1) results were compared with previously obtained data. An increase in IGF-1 and copeptin was seen at 3 and 6 months’ treatment compared to baseline. Between the 3 and 6 months follow up, copeptin levels were stable. There was a difference in HbA1c between 3 and 6 months (p < 0.01) and between baseline and 6 months (p = 0.042), with higher levels at 6 months. In addition, LDL levels were lower at the 6 months follow up (p = 0.046). The waist circumference at 3 months was lower (p = 0.02). To conclude, three months of GH treatment increased the levels of copeptin and the increase remained at 6 months. This could be a compensatory mechanism balancing the anti-natriuretic effect of GH treatment seen in previous studies.

Cardiac functions in children with growth hormone deficiency: Effects of one year of GH replacement therapy

IntroductionChildren with Growth Hormone deficiency (GHD) are prone to heart dysfunction and, if left untreated, will result in marked cardiac dysfunction in adulthood. The aim was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiac structure in children and adolescents, and to investigate the role of insulin like growth factor-1 (IGF-1) in this. MethodsM-mode, pulse-wave Doppler echocardiography and tissue Doppler imaging (TDI) were performed in 49 children with GHD who were divided into those with a peak GH response < 7 μg/L and 7–10 μg/L after two GH stimulation tests, aged 8–16 years at baseline and at six and 12 months after GH initiation, and 49 healthy peers. IGF-1 concentration was measured. ResultsAlthough the left ventricular end diastolic and systolic diameters in both GH deficient groups were significantly lower than controls (p < 0.01), both diameters increased significantly with one year of treatment and achieved normal values (p > 0.05). Using TDI in both two patients group revealed increased E/A, prolonged isovolumic relaxation time, shortened ejection time, and a significant increase in myocardial performance index compared to controls (p < 0.001). Significant improvement was observed in these parameters from the sixth month of GH treatment (p < 0.001), this improvement does not match parameters measured in healthy peers, even after one year of treatment in both patients group. (p < 0.001). No correlation was found between IGF-1 concentration and any echocardiographic parameter. ConclusionEchocardiographic parameters were similar in children with a GH peak < 7 μg/L and 7–10 μg/L. In TDI, both systolic and diastolic function was impaired in GHD children compared to controls. These parameters improved after one year of GH therapy but did not recover to healthy control levels.

Growth Hormone Treatment for Adults With Prader-Willi Syndrome: A Meta-Analysis.

ContextFeatures of Prader-Willi syndrome (PWS) overlap with features of growth hormone (GH) deficiency, like small hands and feet, short stature, increased body fat, and low muscle mass and strength. In children with PWS, GH treatment (GHt) improves physical health and cognition. GHt has become the standard of care in PWS children, but in adults this is not yet the case.ObjectiveThis work aims to provide an overview of the current knowledge on GHt in PWS adults.MethodsMedline, Embase, and the Cochrane Central Register of Controlled Trials databases were searched. Study selection included randomized clinical trials (RCTs) and nonrandomized (un)controlled trials (NRCTs) that reported data for adults with PWS, who received GHt for at least 6 months. Data on body composition, body mass index (BMI), cardiovascular end points, bone, cognitive function, quality of life, and safety were extracted.ResultsNine RCTs and 20 NRCTs were included. Body composition improved during 12 months of GHt with an increase in mean (95% CI) lean body mass of 1.95 kg (0.04 to 3.87 kg) and a reduction of mean (95% CI) fat mass of –2.23% (–4.10% to –0.36%). BMI, low-density lipoprotein cholesterol levels, fasting glucose levels, and bone mineral density did not change during GHt. There were no major safety issues.ConclusionGHt appears to be safe and improves body composition in adults with PWS. Because poor body composition is closely linked to the observed high incidence of cardiovascular morbidity in adults with PWS, improving body composition might reduce cardiovascular complications in this vulnerable patient group.

Comparison of Quality of Life Responses From Caregiver and Children Aged ≥7 Years Using the Quality of Life in Short Stature Youth (QoLISSY) Questionnaire, Following 12 Months of Growth Hormone Treatment With Either a Weekly Somatrogon or a Daily Genotropin Injection Schedule

Objective: Paediatric growth hormone deficiency (pGHD) affects 1/4,000 children. Treatment with daily sub-cutaneous injections of recombinant human growth hormone (r-hGH) increase height velocity and quality of life (QoL). A recent randomised controlled clinical trial (NCT02968004) evaluated the efficacy/safety of weekly Somatrogon (hGH-CTP) and daily Genotropin in pGHD. QoL (an exploratory endpoint) was evaluated using the validated Quality of Life in Short Stature Youth (QoLISSY) questionnaire, which includes three subscales (physical, social, emotional) and total score. Methods: The QoLISSY core module was administered to patients (aged 3-11 years [girls], 3-12 years [boys]) and parents in US, UK, Australia, New Zealand, Belarus, Russia, Ukraine and Spain, at Baseline (BL) and 12 months after treatment start. The QoLISSY-CHILD was completed by children aged ≥7 years; QoLISSY-PARENT was completed by the Caregiver for children <7 years, and for some children aged ≥7 years. We report here only the QoLISSY results for children aged ≥7 years (reported from either child or parent). Results: For Total QoLISSY-PARENT, for children aged ≥7 years in the Somatrogon group (N=26), mean scores are 53.65 (BL) and 65.52 (month 12) with mean change of 13.01 (95% Confidence Interval [CI]: 3.99, 22.02). In the Genotropin group (N=28), mean scores are 55.89 (BL) and 63.66 (month 12) with mean change of 6.60 (CI:-0.21, 13.40). For Total QoLISSY-CHILD in the Somatrogon group (N=35), mean scores are 61.48 (BL) and 74.69 (month 12) with mean change of 13.00 (CI: 5.81, 20.19). In the Genotropin group (N=35), these scores are 60.96 (BL) and 69.03 (Month 12) with mean change of 7.84 (CI: 2.71, 12.97). Scores of >70 indicate a good QoL. Conclusions: QoL in children aged ≥7 years improved, following 12 months of either treatment, whether this was reported by caregiver or child. However, these data show that the baseline scores and 12 month scores from the QoLISSY-PARENT in both treatment groups were numerically lower than those reported by the child. This is consistent with the literature¹, in which the caregivers generally report lower QoL scores on behalf of the child.¹Explaining parent-child (dis)agreement in generic and short stature-specific health-related quality of life reports: do family and social relationships matter? Quitmann et al Health and Quality of Life Outcomes 2016 vol 14, Article 150

PDB4 Evaluation of Quality of Life in PRE-Pubertal Children Using the Quality of Life in Short Stature Youth (QOLISSY) Questionnaire, Following 12 Months of Growth Hormone Treatment with Either a Weekly Somatrogon or a Daily Genotropin Injection Schedule

Paediatric growth hormone deficiency (pGHD) affects 1/4,000 children. Treatment with daily sub-cutaneous injections of recombinant human growth hormone (r-hGH) increase height velocity and quality of life (QoL). However, adherence to daily r-hGH varies; one study reported 66% of children were non-compliant (>1 injection/ week missed)1. A recent randomised controlled clinical trial (NCT02968004) evaluated the efficacy/safety of weekly Somatrogon (hGH-CTP) and daily Genotropin in pGHD. QoL (an exploratory endpoint) was evaluated using the validated Quality of Life in Short Stature Youth (QoLISSY) questionnaire, which includes three subscales (physical, social, emotional) and total score. The QoLISSY core module was administered to patients (aged 3-11 years [girls], 3-12 years [boys]) and parents in eight countries, at Baseline (BL) and 12 months after treatment start. The QoLISSY-CHILD was completed by children aged ≥7 years; QoLISSY-PARENT was completed by the Caregiver for children < 7 years. For Total QoLISSY-PARENT, in the Somatrogon group (N=19), mean scores are 61.82 (BL) and 69.49 (month 12) with mean change of 8.48 (95% Confidence Interval [CI]: 1.06, 15.89). In the Genotropin group (N=28), mean scores are 54.58 (BL) and 63.80 (month 12) with mean change of 8.51 (CI: 2.27, 14.74). For Total QoLISSY-CHILD (> 70% male), in the Somatrogon group (N=35), mean scores are 61.48 (BL) and 74.69 (month 12) with mean change of 13.00 (CI: 5.81, 20.19). In the Genotropin group (N=35), these scores are 60.96 (BL) and 69.03 (Month 12) with mean change of 7.84 (CI: 2.71, 12.97). All three sub-scales (both QoLISSY versions) showed similar trends in improvement over 12 months. Scores of >70 indicate a good QoL. QoLISSY-CHILD and QoLISSY-PARENT demonstrated comparable QoL improvements for children with pGHD by end of Month 12 in weekly Somatrogon and daily Genotropin treated groups. 1Cutfield et al PLoS ONE 6.1 (2011): 1-3.

S0514 Growth Hormone Normalizes Gastrointestinal Symptoms in mTBI Patients

INTRODUCTION: Chronic inflammatory processes secondary to brain trauma have been hypothesized to significantly alter gastrointestinal metabolism, motility, and microbiome composition in patients with mild traumatic brain injuries (mTBI). This may be exacerbated by pituitary dysfunction and decreased growth hormone (GH) secretion resulting from injury. In this clinical trial, we analyzed the effects of GH treatment on gastrointestinal symptoms experienced by patients with concurrent mTBI and abnormal GH secretion. METHODS: Adult patients with mTBI and peak GH levels of < 10 ng/mL following glucagon stimulation test (n = 10) were given 0.6 mg injections of recombinant human growth hormone (rhGH) daily over a 6 month period. These patients were matched with healthy household controls (HHC) with whom they resided and shared meals with for comparison (Table 1). The Gastrointestinal Symptom Rating Scale (GSRS) measuring constipation, diarrhea, indigestion, abdominal pain, and acid reflux was administered to mTBI subjects (n = 10) and their healthy household controls (HHC; n = 10) every month for 6 months. RESULTS: GSRS scores within the treatment group dropped significantly after only one month of GH treatment (Figure 1, P < 0.01). Although GSRS scores were higher than the HCCs at baseline, the GSRS score of mTBI patients did not differ from the HHCs after receiving GH therapy. GSRS scores of the HHCs did not change significantly throughout the duration of the study (P > 0.05). CONCLUSION: Growth hormone may play a novel role in altering relationships in the gut-brain axis. Our results suggest that GH treatment helps to reduce a myriad of gastrointestinal symptoms in mTBI patients. We speculate this improvement may be attributable to changes in gut flora and overall gut microenvironment in mTBI, resembling that of healthy controls. Future studies can characterize the bacterial composition of gastrointestinal microbiomes of mTBI patients pre- and post-hormone supplementation compared to healthy controls to confirm this hypothesis.Table 1.: Demographics for healthy household controls and mTBI patients enrolled in the study (n = 20) a- Fisher's exact test; b- Parametric unpaired t-testFigure 1.: Gastrointestinal symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS) in mTBI patients receiving 6 months of growth hormone treatment compared to matched healthy household controls.

Growth hormone rescue cerebellar degeneration in SCA3 transgenic mice

Spinocerebellar ataxia type 3 (SCA3) is a fatal neurodegenerative disease for which no identified effective treatment or prevention methods exist. However, low-dose growth hormone (GH) therapy, as a potential off-label use, may deter the progress of SCA3. SCA3 15Q and SCA3 84Q transgenic mice harboring a YAC transgene that expresses the human ATXN3 gene with a pathogenic expanded 15 CAG repeat and 84 CAG repeat motif, respectively, were recruited. SCA3 15Q transgenic mice were considered as the healthy control group, whereas low-dose GH- and PBS-treated SCA3 84Q transgenic mice were considered as the study and sham groups, respectively. The SCA3 84Q transgenic mice were administered intraperitoneal injections of GH or PBS weekly from the postnatal age of 9 months–18 months. After 9 months of GH treatment in the SCA3 84Q transgenic mice, all locomotor functions including rotarod test, behavior box analysis were restored. The GH-treated SCA3 84Q transgenic mice revealed more preserved Purkinje cells/cerebellar cortex and less ataxin-3 aggregation, DNA oxidative, cell apoptosis compared with the PBS-treated SCA3 84Q transgenic mice. GH therapy may be one of the potential off-labeled using in the alleviation of SCA3 progression.

Evaluation of Safety and Efficacy of Growth Hormone Therapy by IGF-1 Z Score in Children with Short Stature.

This study aims to explore the safety and efficacy of growth hormone (GH) therapy by retrospectively analyzing the changes of insulin-like growth factor-1 (IGF-1) Z-scores in children with short stature after treatment with GH. The etiology of 104 children with short stature was classified according to the GH stimulation test and IGF-1 levels: (1) growth hormone deficiency (GHD); (2) mild growth hormone deficiency (M-GHD); (3) idiopathic short stature (ISS); (4) GH insensitivity syndrome (GHIS). In addition, all patients were treated with recombinant human growth hormone (rhGH) for 12months, and the growth rate (Gv), height, body mass, bone age, height standard deviation scores (HtSDS), IGF-1 and adverse reactions were compared among these three groups before and after treatment. The height, body mass, Gv and HtSDS were significantly higher in each group compared with those before treatment. Furthermore, the Z-score of IGF-1 significantly increased after 1month of GH treatment and was positively correlated with the dosage of GH. Moreover, the difference in standard deviation score was significantly positively correlated with the increase in standard deviation score of IGF-1. The detection of the GH-IGF-1 axis function can be carried out for the etiologic diagnosis of short stature. IGF-1 increased after rhGH treatment, and IGF-1 level was correlated to the time of therapy and dosage of GH. IGF-1-based GH dosing targeted to age- and gender-adjusted means may save medical costs and offer a more dose-sparing and potentially safer mode of therapy compared with traditional weight-based dosing.

Comparison between euglycemic hyperinsulinemic clamp and surrogate indices of insulin sensitivity in children with growth hormone deficiency

ObjectiveData about the impact of growth hormone treatment (GHT) on insulin sensitivity in children are quite controversial, due to the different surrogate indices that have been used. DesignWe evaluated insulin sensitivity through the euglycemic hyperinsulinemic clamp, considered the gold standard technique, in 23 children affected by growth hormone deficiency (GHD) at baseline and after 12months of GHT and in 12 controls with short stature at baseline, and we compared the clamp-derived index (M-value) with the most commonly used surrogate index of insulin sensitivity, as ISI Matsuda, and with circulating plasma markers of insulin sensitivity, as adiponectin and resistin levels. ResultsAt baseline, no significant difference in all metabolic parameters between GHD children and control subjects was found. After 12months of GHT, GHD children showed a significant increase in fasting insulin (p<0.001) and resistin (p=0.028) and a decrease in ISI Matsuda (p<0.001) and M-value (p<0.001), without significant change in fasting glucose, HbA1c and adiponectin. In GHD children, M-value showed a significant but weak correlation with ISI Matsuda (rho 0.418, p=0.047) at baseline, while no correlation with other parameters was found. After 12months of GHT, M-value did not show any significant correlation with any other metabolic parameter analyzed. ConclusionsThis study highlights the limit of the evaluation of insulin sensitivity performed through surrogate indices or circulating markers, which may lead to controversial data and do not correlate with the gold standard technique to evaluate insulin sensitivity.

Growth hormone (GH) enhances anaerobic capacity: impact on physical function and quality of life in adults with GH deficiency.

Anaerobic capacity is impaired in adults with GH deficiency (GHD), adversely affecting physical function and quality of life (QoL). To investigate whether GH replacement improves anaerobic capacity, physical function and QoL in adults with GHD. One-month double-blind placebo-controlled crossover study of GH (0·5mg/day), followed by a 6-month open phase. A total of 18 adults with GHD. Anaerobic power (watts) was assessed by the 30-s Wingate test, and aerobic capacity by the VO2 max (l/min) test. Physical functional was assessed by the stair climb test, chair stand test, 7-day pedometry and QoL by the AGHDA questionnaire. Lean body mass (LBM) was quantified by dual-energy X-ray absorptiometry. GH replacement normalized IGF-1 levels during both study phases. During the 1-month placebo-controlled study, improvement in stair climb and chair stand performance was observed during GH and placebo treatment; however, there were no significant GH effects observed in any outcome measure compared to placebo. Six months of GH treatment significantly increased anaerobic power (P<0·05), chair stand repetitions (P<0·0001), daily step count (P<0·05) and QoL scores (P<0·001) compared to baseline measurements. GH treatment did not significantly improve VO2 max. Improvement in anaerobic power independently predicted an improvement in energy and vitality domain of QoL (P=0·03). GH replacement improves anaerobic capacity, physical function and QoL in a time-dependent manner in adults with GHD. Improvement in the anaerobic but not aerobic energy system is likely to underlie the improvement in QoL in patients with GHD during GH replacement.

A 2-year multicentre, open-label, randomized, controlled study of growth hormone (Genotropin®) treatment in very young children born small for gestational age: Early Growth and Neurodevelopment (EGN) Study.

In Europe, growth hormone (GH) treatment for children born small for gestational age (SGA) can only be initiated after 4 years of age. However, younger age at treatment initiation is a predictor of favourable response. To assess the effect of GH treatment on early growth and cognitive functioning in very young (<30 months), short-stature children born SGA. A 2-year, randomized controlled, multicentre study (NCT00627523; EGN study), in which patients received either GH treatment or no treatment for 24 months. Children aged 19-29 months diagnosed as SGA at birth, and for whom sufficient early growth data were available, were eligible. Patients were randomized (1:1) to GH treatment (Genotropin®, Pfizer Inc.) at a dose of 0·035 mg/kg/day by subcutaneous injection, or no treatment. The primary objective was to assess the change from baseline in height standard deviation score (SDS) after 24 months of GH treatment. Change from baseline in height SDS was significantly greater in the GH treatment vs control group at both month 12 (1·03 vs 0·14) and month 24 (1·63 vs 0·43; both P < 0·001). Growth velocity SDS was significantly higher in the GH treatment vs control group at 12 months (P < 0·001), but not at 24 months. There was no significant difference in mental or psychomotor development indices between the two groups. GH treatment for 24 months in very young short-stature children born SGA resulted in a significant increase in height SDS compared with no treatment.

Low myocardial glucose uptake in Turner syndrome is unaffected by growth hormone: a randomized, placebo-controlled FDG-PET study.

An unfavourable cardiovascular and metabolic phenotype causes threefold excess mortality in Turner syndrome (TS), and perturbed cardiac substrate metabolism is increasingly recognized as a common component of cardiovascular and metabolic diseases. We therefore hypothesized that myocardial glucose uptake (MGU) is reduced in TS and that growth hormone (GH) treatment improves MGU. To this end, this controlled trial elucidates MGU in TS and the impact of 6 months of growth hormone treatment on MGU. Women with TS (n = 9) were examined at baseline, sequentially treated with either Norditropin(®) SimpleXx or placebo and re-examined after 6 months. MGU and myocardial blood flow (MBF) were measured using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) during a hyperinsulinaemic euglycaemic clamp (at baseline and 6 months). Blood pressure measurement, blood sampling, echocardiography and dual energy X-ray absorptiometry scan were also performed. Age-matched female controls (n = 9) were examined once. Baseline MGU was reduced in TS (0.24 ± 0.08 vs. 0.36 ± 0.13 μmol/g/min in controls; P = 0.036) despite similar insulin sensitivity (whole body glucose uptake (M-value): 9.69 ± 1.86 vs. 9.86 ± 2.58 mg/(min*kg) in controls; P = 0.9). Six months of GH carried no impact on MGU (0.25 ± 0.08 vs. 0.26 ± 0.12 μmol/g/min in the placebo group; P = 0.8). Plasma glucose, low-density cholesterol and triglycerides increased, while M-value and exercise capacity decreased during 6 months of GH treatment. MGU is reduced in TS despite normal insulin sensitivity. GH treatment does not alter MGU despite decreased whole body insulin sensitivity. A perturbed cardiac glucose uptake appears to be a feature of TS.

Ovarian morphology and function during growth hormone therapy of short girls born small for gestational age

To study the effect of growth hormone (GH) treatment on ovarian and uterine morphology and function in short, prepubertal small-for-gestational-age (SGA) girls. A multinational, randomized controlled trial on safety and efficacy of GH therapy in short, prepubertal children born SGA. Not applicable. A subgroup of 18 Danish girls born SGA included in North European SGA Study (NESGAS). One year of GH treatment (67 μg/kg/day) followed by 2 years of randomized GH treatment (67 μg/kg/day, 35 μg/kg/day, or IGF-I titrated). Data on anthropometrics, reproductive hormones, and ultrasonographic examination of the internal genitalia were collected during 36 months of GH treatment. Uterine and ovarian volume increased significantly during 3 years of treatment (64% and 110%, respectively) but remained low within normal reference ranges. Ovarian follicles became visible in 58% after 1 year compared with 28% before GH therapy. Anti-Müllerian hormone increased significantly during the 3 years of GH therapy but remained within the normal range. Precocious puberty was observed in one girl; another girl developed multicystic ovaries. GH treatment was associated with statistically significant growth of the internal genitalia, but remained within the normal range. As altered pubertal development and ovarian morphology were found in 2 of 18 girls, monitoring of puberty and ovarian function during GH therapy in SGA girls is prudent. Altogether, the findings are reassuring. However, long-term effects of GH treatment on adult reproductive function remain unknown. EudraCT 2005-001507-19.

Reduction in insulin sensitivity and inadequate β-cell capacity to counteract the increase in insulin resistance in children with idiopathic growth hormone deficiency during 12 months of growth hormone treatment.

To evaluate the performance of various indexes of insulin sensitivity and secretion and to identify the most useful indicator of deterioration of glucose metabolism in a cohort of children with growth hormone (GH) deficiency (GHD) during GH treatment. In 73 GHD children (55 M, 18 F; mean age 10.5 years) at baseline and after 12 months of treatment, we evaluated a number of surrogate indexes of insulin secretion and sensitivity. In a subgroup of 11 children we also performed an euglycemic hyperinsulinemic clamp. After 12 months, a significant increase in fasting glucose (p < 0.001) and HbA1c levels (p < 0.001) was documented, despite all children remained with a normal glucose tolerance. With regard the insulin secretion, Homa-β did not show any significant change (p = 0.073), while oral disposition index (DIo) showed a significant decrease (p = 0.031). With regard the insulin sensitivity, Homa-IR significantly increased (p < 0.001) with a concomitant decrease in QUICKI (p < 0.001). ISI Matsuda showed a decrease, although not statistically significant (p = 0.069). In the subgroup of 11 children, the M value derived from clamp showed a significant decrease (p = 0.011) and a significant positive correlation was found between M value and ISI Matsuda both at baseline (ρ 0.950; p = 0.001) and after 12 months (ρ 0.980; p = 0.001) but not with Homa-IR and QUICKI. 12 months of GH treatment lead to a decrease in insulin sensitivity and impairment in insulin secretion relative to insulin sensitivity even without evident changes in glucose tolerance. DIo has proven to be the most useful indicator of deterioration of glucose metabolism even in cases in which the overt glucose abnormalities have not yet appeared.

Circulating asymmetric dimethylarginine and lipid profile in pre-pubertal children with growth hormone deficiency: Effect of 12-month growth hormone replacement therapy

ObjectiveGrowth hormone deficiency (GHD) in adults is associated with cardiovascular complications, which lead to reduced life expectancy. At present, data on cardiovascular risk factors in GHD children are limited. The aim of this study was to evaluate whether pre-pubertal GHD children have increased cardiovascular risk factors, and whether 12-month growth hormone (GH) treatment can reverse them. DesignTwenty pre-pubertal GHD children (6 boys, mean (±SD) age: 9.5±1.8years) were matched for sex and age with 20 healthy controls (6 boys, mean (±SD) age: 8.8±1.5years). Asymmetric dimethylarginine (ADMA), lipid profile, glucose metabolism parameters, IGF-1, blood pressure and anthropometric parameters were assessed at baseline and after 12months of GH treatment. ResultsAt baseline, GHD patients showed significantly higher ADMA levels (median [interquartile range]: 78.5 [69.6–123.5] vs 54.0 [38.3–60.8] ng/ml, p<0.001), total cholesterol (mean±SD: 177.5±30.4 vs 150.1±21.4mg/dl; p=0.004) and LDL-cholesterol (mean±SD: 111.2±22.2 vs 84.9±15.9mg/dl; p<0.001) than controls. After 12-month GH treatment, ADMA (median [interquartile range]: 55.4 [51.2–73.8] ng/ml), total cholesterol (mean±SD: 155.6±43.2mg/dl), and LDL-cholesterol (mean±SD: 95.4±32.1mg/dl) significantly decreased in GHD children, reaching values comparable to those in controls. ConclusionsThis study showed that, as in adults, pre-pubertal GHD children manifest increased cardiovascular risk markers and that 12-month GH treatment can improve them.

Modification of the Metabolomic Profile Induced by Chronic Growth Hormone Administration in a Doping Model

IntroductionHorses performance can be enhanced via growth hormone (GH) doping. The detection time for GH in blood is too short to allow detection during competition. GH not only affects the proteosynthesis in cells and tissues but can also cause long term metabolic variations. This study aimed to show the metabolomic modifications occurring after three months of GH treatment.MethodsThe study was performed on 20 Welsh ponies. 10 were injected with REPORCIN TM, an approved recombinant GH (30 mg.kg−1 per day) for 3 months and the other 10 comprised the control group. Blood samples were collected before GH treatment (T0), then 3 months later (T3). The NMR spectra acquired on the 40 serum samples were classified according to the factors (season, GH treatment) using the supervised multivariate orthogonal projection on latent structure (OPLS) method. A first OPLS model was computed with the control ponies (T0‐T3). The predictive component of this model was subtracted from the whole data (treated, controls at T0 and T3) to only retain the GH‐dependent variations.ResultsBefore filtering seasonal effects, glucose, lipids and phospholipids were metabolites discriminating between T0 and T3 samples. After removing the seasonal effect, the OPLS model revealed the effect of GH treatment on protein metabolism through the modification of aromatic amino acids and branched chain amino acids. The variations of other metabolites (glycoproteins and lactate) were enhanced.ConclusionsThis study showed that chronic GH injection induced systemic metabolism modifications that can be detected using the NMR metabolomic method without neglecting the misleading effect of season.Ethical Animal ResearchStudies approved by “Comité regional d′éthique pour l′expérimentation animale Centre Limousin” Saisine N° CL2008_015. Sources of funding: French Agency against Doping (AFLD). Competing interests: none.

High prevalence of hypovitaminosis D in Sicilian children affected by growth hormone deficiency and its improvement after 12 months of replacement treatment.

Although the correlation between vitamin D and growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis is documented, as of date, few and conflicting studies have prospectively analyzed vitamin D before and after GH treatment. Our aim was to evaluate as to how the condition of GH deficiency (GHD) or GH treatment influences vitamin D in children. Eighty Sicilian GHD children (M/F 58/22; mean age 10.3 years), grouped according to the season of evaluation in group A (June-September; 41 children) and group B (November-February; 39 children), were evaluated at baseline and after 12 months of GH treatment. Twenty-eight children (35 %) were vitamin D insufficient and 32 (40 %) deficient at baseline, and lower vitamin D levels were found in group B than in A (17.3 ± 5.3 vs. 31.1 ± 11.1 ng/ml; p < 0.001). A positive correlation between vitamin D and baseline GH levels (p < 0.001) was found. After 12 months, increased vitamin D was found both in all children (34.4 ± 16.4 vs. 24.5 ± 11.1 ng/ml; p = 0.002) and in group A (38.5 ± 14 vs. 31.1 ± 11.1 ng/ml; p < 0.001) and B (30 ± 17.7 vs. 17.3 ± 5.3 ng/ml; p < 0.001). Overall, only 25 (31 %) children remained insufficient and 15 (19 %) deficient, with an increase in prevalence of children with normal levels (p = 0.001). Our data demonstrated a very high prevalence of hypovitaminosis D in Sicilian GHD children, with an improvement after 12 months of GH treatment. Vitamin D assessment should therefore be considered routinely in GHD children both at diagnosis and during the follow-up.